CZ301499B6 - Medicament for treating high blood pressure - Google Patents

Abstract

In the present invention, there is disclosed the use of benzazepine-N-acetic acid derivatives, which contain in {alpha} position to a nitrogen atom an oxo group and in position 3 they are substituted with 1-(carboxyalkyl)cyclopentylcarbonyl amine residue, a salt as well as biolabile esters thereof for the preparation of medicaments intended for treating hypertension, particularly for treating certain forms of secondary hypertension in large mammals and humans wherein the cause of the hypertension being treated can be of various origin.

Description

A medicine for the treatment of high blood pressure

Technical field

The present invention relates to the use of benzazepine-N-acetic acid derivatives which contain an oxo group in the apposition to the nitrogen atom and are substituted in the 3-position with a 1- (carboxyalkyl) cyclopentylcarbonylamine residue, and their salts and biolabile esters for the treatment of high blood pressure. forms of secondary high blood pressure, in larger mammals, and especially humans, and in the manufacture of medicaments suitable for this treatment. The cause of the blood pressure to be treated may have different origins. In particular, the invention relates to the treatment of those forms of secondary high blood pressure that may occur as a result of various non-cardiac diseases.

Background Art

Benzazepine-N-acetic acid derivatives containing an oxo group in the α-position to the nitrogen atom and in the 3-position are substituted with a 1- (carboxyalkyl) cyclopentylcarbonylamino radical, and whose salts and biolabile esters fall within the protective range of benzazepine, benzoxa-zepine derivatives and benzothiazepine-N-acetic acids described in German patent application DE 195 10 566, which contain an oxo group in the α-position to the nitrogen and in the 3-position are substituted with 1 (carboxy alkyl) cyclopentylcarbonylamines and have NEP-inhibitory effects. The benzazepine-N-acetic acid compounds used in the present invention can be prepared by the processes described in Db 195 10 50.

It is an object of the present invention to provide novel pharmaceutical compositions for the treatment of high blood pressure, particularly for the treatment of certain forms of secondary high blood pressure. Preferably, this object of the invention relates to the development of new pharmaceutical compositions for the treatment of forms of secondary high blood pressure which may occur as a result of various non-cardiac diseases.

SUMMARY OF THE INVENTION

According to the invention, the compounds of the formula I are now used

R ¹ represents a lower alkyl group (C 1 -C 4 -alkyl) which may optionally be substituted in the phenyl ring by C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy or halogen, or represents a naphthyl group (C 1 -C 4 -alkyl),

- 1 GB 301499 B6

R 'is hydrogen or a biolabile ester forming group; and

R 'represents hydrogen or a biolabile ester-forming group, wherein the biolabile ester-forming group in R ² and / or R ³ represents a C 1 -C 4 alkyl group, optionally in a ring-bitch or phenyl- (C 1 -C 4 alkyl) group or via 2 adjacent substituted C1-C4 alkylene chain substituted phenyl or C1-C4 alkyl, especially phenyl. benzyl or indanyl, dioxolanyl · methyl group optionally substituted in the dioxolane ring Cl to C4 alkyl, zejméio to (2.2-dimethyl-L3 dio \ olan_4-yl) inethylskupinou, or represents a C2-C6 ^alpha LK ^yes ° ^x ymethylskupinu yl, optionally substituted and a physiologically compatible salt of the acids of formula I for the manufacture of a medicament for the treatment of high blood pressure, particularly those forms of secondary high blood pressure which are caused by non-cardiac diseases in larger mammals and humans.

When in the compounds of formula I the substituents in question represent or contain lower alkyl or alkoxy groups, they may be straight-chain or branched and contain, in particular, 1 to 4, preferably 1 to 2, carbon atoms and preferably represent methyl or methoxy. If the substituents contain halogen, in particular fluorine, chlorine or bromine, preferably fluorine or chlorine, are suitable.

The radical R ¹ may be a lower alkylene chain containing 1-4, preferably 1-2 carbon atoms. In particular, R ¹ represents an optionally substituted phenethyl group, which may optionally be substituted one or more times with halogen, lower alkoxy or lower alkyl or the corresponding naphthylethyl group.

The compounds of formula 1 are optionally esterified di-carbonic acid derivatives. According to the form of administration, preferred are biolabile monoesters, especially compounds wherein R is a biolabile ester forming group and R ^{3 is} hydrogen, or dicarboxylic acids, the latter being particularly suitable for in vivo applications.

Suitable alkyl groups suitable for R ² and R ³ are the lower alkyl groups, optionally in the phenyl group by phenyl- or phenyl-lower alkyl groups substituted by a lower alkyl group, or a phenyl- or phenyl-linked lower alkylene chain bonded via one of the two adjacent carbon atoms Is lower alkyl, in the dioxolane ring, optionally lower alkyl substituted with dioxolanes by Imethyl, or alternatively on the oxymethyl group lower alkyl substituted by C 1 -C 6 -alkanoyloxymethyl. When the R ² or R ³ forming the biolabile ester is lower alkyl, it may preferably be a straight chain alkyl group having 1 to 4, preferably carbon atoms. If the biolabile ester forming group is an optionally substituted phenyl-lower alkyl group, its alkylene chain may contain 1 to 3, preferably 1, carbon atoms. If the phenyl ring is substituted by a lower alkylene chain, it may contain 3 to 4, in particular 3, carbon atoms. As substituents R ² and / or R ³ contains a phenyl group is particularly useful phenyl, benzyl or indanyl. When R ² and / or R ³ optionally substituted alkanoyloxvmethylskupinu displayed, its alkanoyloxy group can contain 2 to 6, preferably 3 to

5, carbon atoms and is preferably branched and may, for example, be a pivaloyloxymethyl radical (tert-butylcarbonyloxymethyl radical).

Suitable physiologically compatible salts of the dicarboxylic acids or monoesters of the formula I are their alkali, alkaline-earth or ammonium salts, e.g. sodium or potassium salts or salts with physiologically compatible, pharmacologically neutral organic amines such as, for example, diethylamine or tert. -buty lamin.

The compounds of formula (I) contain two chiral carbon atoms, namely a carbon atom bearing a side amide chain at the ring position and a residue R bearing a side chain amide chain carbon atom 55c. Thus, these compounds may exist in several optically active stereoisomeric forms or racemates. According to the present invention, both racemic mixtures and isomerically pure compounds of formula I may be used.

It has now surprisingly been found that the group of compounds of the formula I used according to the invention, in particular also with respect to certain secondary forms of high blood pressure - has a blood pressure reducing effect on humans and larger mammals. The compounds of formula I and their biolabile esters are thus suitable for the treatment of high blood pressure, in particular for the treatment of certain forms of secondary high blood pressure, wherein the high blood pressure to be treated may be of various origins. The compounds of the formula, including their acid salts and biolabile esters, are preferably used to treat those forms of secondary high blood pressure that may occur as a result of various non-cardiac diseases.

High blood pressure (hypertonia) refers to an increase in blood pressure above a given norm, which mainly occurs as arterial hypertonia. With respect to the cause of high blood pressure, two major forms are distinguished: primary or primary high blood pressure on the one hand and forms of secondary high blood pressure on the other. Basically, high blood pressure is due to increased flow resistance due to initially purely functional, later organic narrowing of the arterial blood pathway. On the other hand, secondary or also symptomatic high blood pressure is bound to a particular organ, i. high blood pressure released by the organ of the competent authority, which may appear, inter alia, as endocrine, renal, pulmonary or cardiovascular hypertonia. These causally responsible for secondary high blood pressure may be of a multifaceted nature, e.g. chronic obstructive pulmonary and respiratory diseases or chronic asthma. Thus, normal blood circulation in the lungs of an adult human occurs at low pressure and low resistance. However, persistent chronic hypoxia, such as may occur in chronic obstructive airway diseases, leads to pulmonary arterial hypertension and pulmonary arterial remodeling (increased vascular muscle cell growth) and right ventricle (increased cardiac muscle cell growth).

Particularly preferably, the compounds of formula I, including their salts of the respective acids and their biolabile esters, can be used for the treatment of pulmonary high blood pressure, in particular of non-cardiac origin. Pulmonary hypertension can exist as a primary form (of unknown cause) or as secondary pulmonary hypertension and can be treated with compounds of formula 1 and their physiologically compatible salts of the acids and their biolabile esters.

By (secondary) pulmonary high blood pressure (high pressure in a small cycle) is meant a constant increase in mean pulmonary arterial pressure to values > 22 mm Hg at rest. This increase in mean pressure may occur, for example, due to heart-related backflow in a small cycle (eg mitralvicia, left heart insufficiency), vascular cross-linking in the capillary region (eg due to hypoxia when staying at high altitude, obstructive emphysema, lung-reducing operations), secondary vascular loss (in pulmonary fibrosis, destructive emphysema), hypercirculation in the lung cycle with the following vasoconstrictor disease (eg, heart failure with a large right-to-left shunt), recurrent pulmonary embolism, as a side effect in taking certain appetite suppressants (eg, Aminorex) or also due to primary constriction pulmonary vessels (= idiopathic = primarily vascular pulmonary high pressure).

In the treatment of high blood pressure according to the invention, the compounds of formula I and their physiologically compatible salts of the acids and their biolabile esters in conventional pharmaceutical preparations can be administered orally, intravenously or also transdermally.

Thus, the compounds of formula 1 and their physiologically compatible salts of said acids and their biolabile esters may be contained in an effective blood pressure reducing amount together with the usual pharmaceutical excipients and / or carriers in solid or liquid pharmaceutical preparations. Examples of solid preparations are orally administrable preparations such as tablets, dragees, capsules, powders or granules, or also suppositories or patches (transdermal tera-3 systems 301499 B6). These solid preparations may contain pharmaceutically customary inorganic and / or organic carriers such as milk sugar, talc or starch in addition to pharmaceutically customary excipients such as anti-sticking or tablet disintegrants. Liquid preparations such as solutions, suspensions or emulsions of the active compounds may contain conventional diluents such as water, oils and / or suspensions, such as polyethylene glycols and the like. In addition, other adjuvants may be added, such as preservatives, odor control agents, and the like.

The active compounds can be mixed and formulated in a known manner with pharmaceutical auxiliaries and / or carriers. For the production of solid pharmaceutical forms, for example, the active substances can be mixed in a customary manner and granulated in wet or dry form with excipients and / or carriers. The granulate or powder may be filled directly into capsules or compressed into tablet cores in a conventional manner. These can, if desired, be filled into the dragee in a known manner. Liquid preparations may be obtained by dissolving or dispersing the active compounds in a suitable liquid carrier in the form of solutions or suspensions.

The blood pressure-lowering effect of the compounds of formula I used according to the invention can be demonstrated in in vivo pharmacological tests in chronically hypoxic rats by measuring the effect of the substance in relation to suitable pharmacological indicators, eg by measuring pulmonary arterial pressure and right ventricular weight. pulmonary vascular remodeling in hypoxic rats.

Description of test methods and results

As a test substance, compounds of formula I (3S, 2R) -3- [1- (2 '- (carbox-4'-phenylbutyl) cyclopentane-1-carbonylamino] -2, 3,4,5-tetrahydro-2-oxo

H-1-Benzazepine-1-acetic acid. The dose administered was 40 mg / kg per day (sufficient to suppress pressure feedback on large endothelin),

Sprague-Dawley rats (260-310 g; n = 6-10 per experimental group) were used as experimental animals. To generate pulmonary high blood pressure, animals were exposed to acutely hypoxic conditions in a pressure chamber. The control group was maintained for comparison under normal air and another control group under hypoxic conditions.

The tests were performed as follows:

The test animals were treated with the active ingredient or appropriate vehicle using osmotic minipumps. The osmotic minipumps were implanted intraprocritonally to the animals before the animals were later housed in a pressure chamber for 2 weeks. There animals were maintained at normal pressure either under hypoxic conditions (10% O ₂ ) or under normal air. After weeks, the animals were prepared for hemodynamic examinations and given measurements.

Hemodynamic examinations

The animals were sacrificed (anesthetized) and then a pre-prepared canvas was inserted through the right jugular vein, atrium and ventricle into the pulmonary artery in the usual manner. A catheter was inserted into the left jugular vein to allow the active substances to be administered intravenously. The left carotid artery was also cannulated to measure systemic blood pressure. Pulmonary artery pressure (PAP) was noted after waking up the animals. Then, the rats were again exposed to hypoxic conditions (10% O ₂ ) in the appropriate mini-chamber for 10 minutes, the increase in pulmonary arterial pressure was measured and also recorded. The effects of the test substance on PAP under normoxic and hypoxic conditions are shown in Tab. 1 compared to control experiments. Data presented are mean ± standard deviations and were statistically evaluated by ANOVA.

-4GB 301499 B6

Measurement of antihyperturbation effect

After hemodynamic examinations, the animals were killed and the hearts were dissected. Weights of right and left ventricles were determined and assembled in relation to body weight. The effects of the test substance on heart weight under normoxic and hypoxic conditions are shown in Tab. 1 compared to control experiments. Data presented are mean ± standard deviations and were statistically evaluated by ANOVA.

Research on the effect on remodeling of the tenen tenen

After the rats were killed, the lungs were isolated in addition to the hearts. These were examined histologically; distal muscularization sites of the lung vessels were determined microscopically at 400 times magnification after van Gieson staining. The effects of the test substance on pulmonary artery remodeling (i.e., distal pulmonary vascularisation) during 2-week hypoxia are shown in Tab. 2 in comparison with hypoxic experiments. Data presented are mean ± standard deviations and were statistically evaluated by ANOVA.

Results:

In the test method described, treatment with test substance in hypoxic animals resulted in a statistically significant reduction in arterial pressure (PAP) compared to hypoxic control animals (Table 1). However, normal systemic blood pressure was not affected; no hypotensive properties were found. This is a particular advantage since there is no risk of a drop in blood pressure below nor25 in normal, pressure-sensitive persons with low blood pressure.

Table 1:

Effects of the substance used (40 mg / kg / day for 14 days) on pulmonary arterial pressure and right and left heart weights in rats under 14-day normoxic and hypoxic conditions.

N ormoxie Hypoxia Parameter Control n = 9 Test substance π = 8 Control n = 10 Test substance n = 9 PAP (mm Hg) 19.9 ± 2 22.2 ± 1 42.9 ± 1.6 * 33.2 ± 1.2 ' RtHWt (mg) 178 ± 10 171 + 10 269 ± 4.5 * 242 ± 0.64 ^m Rt / LtHWt (mg / mg) 0.25 ± 0.01 0.25 ± 0.01 0.45 ± 0.0 1 * 0.40 ± 0.02 ’ RtHWt / -W (mg / g) 0.54 ± 0.02 0.56 ± 0.03 0.94 ± 0.02 * 0.87 ± 0.03 **

The table means:

* significantly different compared to normoxic control (p <0.05) // significantly different compared to hypoxic control (p <0.05) io PAP = pulmonary arterial pressure

RtHWt - right ventricular chamber weight (mg); Rt / LtHWt = right to left ventricular mass ratio; Rt11WT / BW = ratio of right ventricular chamber weight to body weight.

-5GB 301499 Bo

Reduction of pulmonary arterial pressure by the test substance resulted in a statistically significant reduction in right rat heart weight (antihyperthyroid effect) compared to hypoxic controls (Table 1). There has also been a tendency to reduce weight ratios of left heart weight to right heart weight and right heart weight to body weight (Table 1),

Furthermore, the test substance reduced the statistically significant muscularization of the distal lung vessels of the rat (Table 2). This reduced pulmonary-arterial remodeling is also due to a statistically significant reduction in pulmonary high blood pressure.

Table 2;

Effects of a compound used according to the invention (40 mg / kg / day for 14 days) on muscularization of the distal lung vessels of rats during 14-day hypoxia compared to hypoxic control trials

Parameter 14 days of hypoxia Control n = 6 Testing substance n - 6 Muscularized (%) 76 + 4 52 ± 5 ’ Partly muscularized (%) 23 + 4 39 ± 4 * Non-muscularized (%) 1 ± 1 9 + 3

significantly different compared to hypoxic controls (p <0.05)

Because of their above-described effect, the compounds of formula I and their salts and biolabile esters are useful as medicaments for larger mammals and humans for the treatment of high blood pressure, particularly for the treatment of certain forms of secondary high blood pressure. The compounds used according to the invention are particularly suitable for the treatment of those forms of secondary high blood pressure which may occur as a result of various non-cardiac diseases, such as, for example, for the treatment of non-cardiac-related pulmonary high blood pressure. Thus, the substances used according to the invention provide a preferred use for the treatment and / or prevention, in particular of hypoxia-related high blood pressure and its complications, without reducing normal systemic blood pressure.

Here, the dicarboxylic acids of formula I and their salts are conveniently used in parenteral, especially in vivo, administrable dosage forms and the mono- or diesters of formula I conveniently in orally administrable dosage forms. The dosages used may be individual and vary naturally depending on the type of condition being treated, the agent used and the form of administration. E.g. parenteral formulations generally contain less active agents than oral preparations. In general, however, dosage forms containing from 1 to 200 mg per single dose are suitable for administration to larger mammals, particularly humans. The compounds of formula I, including their respective acid salts and their biolabil esters, can be administered in pharmaceutical preparations for both immediate and delayed, controlled and / or controlled release of the active ingredient.

DETAILED DESCRIPTION OF THE INVENTION

The following examples are intended to illustrate the invention in more detail, but are not to be construed as limiting the scope thereof. Used according to the invention

The compounds of the formula I can be prepared by the methods described in the aforementioned patent application DE 195 10 566. Example 3 shows preferred compounds for use according to the invention.

Example I:

Tablets containing (3S, 2 S ') -3- {1 - [2 ^f - (ethoxycarbonyl 1) 4'-phenyl butyl Jcyklopentan 1-amino-1-carbonyl} -2,3,4,5-tetrahydro- 2 oxo 1 H1-benzazepine-1-acetic acid io Tablets were produced as follows per tablet:

(3S, 2'R) 3- {1- [2 '- (ethoxycarbonyl) -4'-phenylbutyl] cyclopentane-1-carbonylamino} -2,5,4,5 tetrahydro-2 H -1-benzazepine- 1-acetic acid 20 mg

Corn starch 60 mg

Milk sugar 135 mg

Gelatin As a 10% solution) 6 mg

The active ingredient, corn starch and milk sugar were concentrated with a 10% gelatin solution. The paste was ground and the resulting granulate was placed on a suitable sheet and dried at 45 ° C. The dried granulate was passed through a pulverizer and mixed in the mixer with the following 20 excipients:

Taiek 5 mg

Magnesium stearate 5 ing

Maize ri-zUi O pl

HUIIUI Ό

And then it was compressed into tablets weighing 240 mg.

Example 2:

Solution for injection containing (3S, 2S ') 3' (2'-carbonyl-N-thenyl-butyl-cyclopentane-1-carbonylamino] -2,3,4,5-tetrahydro-2-oxo-1H-benzazepine-1-acid acetovou.

A solution for injection was made with the following composition per 5 ml:

(3S, 2'R> -3- [1- (2'-Carboxy 4 'phenyl-butyl-cyclopentane-1-carbonylamino) -2,3,4,5-tetrahydro-35-oxo-1H-benzazepin-1-acid) acetic acid 10 mg

Na ₂ HPO _b 7H ₂ O 43.24 mg

NaH ₂ PO ₄ .2H ₂ O 7.72 mg

NaCl 30.0 mg purified water 4948.0 mg

The solids were dissolved in water, the solution was sterilized and filled into ampoules of 5 ml each.

Example 3:

Preferred compounds of formula I for use in the invention for the manufacture of vaccines for the treatment of high blood pressure, in particular for the treatment of secondary forms of high blood pressure, such as pulmonary high blood pressure. for example (including salts of the acids concerned):

Acid 1- {1- [2'-ethoxycarbonyl-4'-phenylbutyl] cyclopentane-1-carbonylamino} -2,3,4,5-tetrahydro-2-oxo-1H-benzazepine-tert-butyl ester octove.

-7EN 301499 B6 (3S, 2R ') -3- {1 - [(2') - (ethoxycarbonyl) -4'-phenylbutyl] cyclopentane-1-carbonyl amino} -2,3,4,5-tetrahydro-2 -oxo-1H-benzazepine-tert-butyl ester 1-acetic acid.

(3S, 2R ') - 3- {1- [2'4-ethoxycarbonyl) -4-phenylbutyl] cyclopentane-1-carbonylamino} -2,3,4,55 tetrahydro-2-oxo-1H-benzazepine-1 -acetic acid.

(3S, 2R ') -3- {1- [2' (carboxy-4-phenylbutyl) cyclopentane-1-carbonylamino} -2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1 - acetic acid.

Acetic acid 3- {1- {2 '- (tert-butoxycarbonyl) -4-phenylbutyl] cyclopentane-1-carbonylamino} -2,3,4,5-tetrahydro-2H-benzazepine-tert-butyl ester.

3- [1- (2-Carboxy-4'-phenylbutyl) cyclopentane-1-carbonylamino] -2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid.

3- {1- [2,4'-tert-butoxycarbonyl) -4'-phenylbutyl] cyclopentane-1-carbonylamino} -2,3,4,5-tetrahydro-2-oxo-1H-benzazepine-benzyl ester-1-acetic acid.

1-Acetic acid 3- [1- (2'-carboxy) -4-phenylbutyl] cyclopentane-1-carbonylamino] -2,3,4,5 tetrahydro-2-oxo-1H-1-benzazepine-benzyl ester.

3- {1- [2 '- (tert-butylcarbonyloxymethoxycarbonyl) -4-phenylbutyl] cyclopentane-1-carbonylamino} -2,3,4,5-tetrahydro-2-oxo-1H-benzazepine-benzyl ester 1 - acetic acid,

3] I- ^[f 2 - (pivaloyl! Oxymethoxykarbonyl) -4-phenylbutyl] cyclopentane-carbonylamino} -2,3,4,5-tetrahydro-2-oxo-1H-benzazepine-l-acetic acid.

Claims (5)

PATENT CLAIMS 4o R ¹ represents a lower alkyl (C 1 -C 4 -alkyl) group which may optionally be substituted in the phenyl ring by a C 1 -C 4 alkyl, a C 1 -C 4 alkoxy or halogen, or a naphthyl (C 1 -C 4 alkyl) group, R ² represents hydrogen or a group forming a biolabile ester, and - 8 GB 301499 B6 R 'is hydrogen or a biolabile ester-forming group, wherein the biolabile ester-forming group in R ² and / or is a C 1 -C 4 alkyl group. optionally 5 in the phenyl ring or in the phenyl (HCl to C4 alkyl) group or via na 2 adjacent carbon atoms bound C1-C4 alkylene chain substituted phenyl or phenyl with C1-C4 alkyl, in particular phenylbenzyl or indanyl, dioxolanylmethyl optionally substituted in the dioxolane by C1-C4 alkyl, in particular (2,2-dimethyl-1, 3) -dioxolan-4-yl) methylkininnii. or represents a C 1 -C 6 -alkanoyloxy group optionally substituted on an oxymethyl group with a lower alkyl group and physiologically compatible salts of the acids of formula 1 for the manufacture of a medicament for the treatment of hypertension, particularly those forms of secondary hypertension mammals and humans. Use of a compound according to claim 1 wherein the secondary, high blood pressure that is caused by non-cardiac disease is pulmonary high blood pressure. Use of a compound according to claim 1 or 2, wherein R ² and / or R ³ is a biolabile ester-forming group as defined in claim 1. Use of compounds according to any one of the preceding claims, wherein R ² is a biolabile ester-forming group and R is hydrogen. Use of the compounds according to claim 4, wherein the compound of the formula I is used 25 (3S, 2R ') -3- {1- [2' - (ethoxycarbonyl) -4-phenyl-butyl] -pentane-1-carbonylamino) -2,3,4,5-tetrahydro-2-oxo-1H 1-benzoic acid 1 acetic acid or a physiologically compatible salt thereof.